Synthesis of 1,2,4-triazines and the triazinoisoquinolinedione DEF ring system of noelaquinone

Article abstract of DOI:10.1039/c2ob25353d

The intramolecular Staudinger-aza-Wittig reaction is used for a general synthesis of 1,2,5,6-tetrahydro-1,2,4-triazines, a structural motif reported for the natural product noelaquinone. The DEF moiety of noelaquinone was obtained in 13 steps and 2% overall yield, and the structure of the synthetic product was confirmed by X-ray analysis.

Full text of DOI:10.1039/c2ob25353d

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COMMUNICATION
Synthesis of 1,2,4-triazines and the triazinoisoquinolinedione DEF ring
system of noelaquinone†‡§
Liming Cao, John P. Maciejewski, Stephan Elzner, David Amantini and Peter Wipf*
Received 20th February 2012, Accepted 19th March 2012
DOI: 10.1039/c2ob25353d
The intramolecular Staudinger-aza-Wittig reaction is used
for a general synthesis of 1,2,5,6-tetrahydro-1,2,4-triazines, a
structural motif reported for the natural product noelaqui-
none. The DEF moiety of noelaquinone was obtained in 13
steps and 2% overall yield, and the structure of the synthetic
Scheme 1 Retrosynthesis of 1,2,5,6-tetrahydro-1,2,4-triazines.
product was confirmed by X-ray analysis.
Noelaquinone 1 (Fig. 1) was isolated in 1998 by Paul Scheuer
and coworkers from the Indonesian Xestospongia sp.1 The struc-
ture assignment of this marine metabolite was mainly based on
NMR analyses, and its biological activities have not yet been
explored. However, the hexacyclic noelaquinone ring system is
closely related to halenaquinone, xestoquinone, and the viridin
class of furanosteroids, many of which have shown potent kinase
inhibitory effects.2,3 A distinct feature of noelaquinone is its
DEF
3,4-dihydro-2H-[1,2,4]triazino[2,3-b]isoquinoline-6,11-
dione, a heterocycle that has hitherto never been synthesized.
The absence of any information on its biological profile and
the presence of a unique heterocyclic ring system make noelaqui-
none an attractive target for total synthesis. Herein, we report
a new method for the formation of fused 1,2,4-triazines and
Scheme 2 Preparation of triazino-isoindolones from N-amino-
phthalimide.
its application to the first preparation of the DEF ring system
in 1.
As a key step for the expedient formation of 1,2,4-triazines,
we planned to develop a variant of the intramolecular Staudin-
ger-aza-Wittig reaction. This method has proven to be a useful
tool in natural products synthesis,4 and we decided to further
explore its application for the ring closure of an azido-hydrazide
precursor (Scheme 1).
Fig. 1 Polycyclic furans isolated from the marine sponge
Xestospongia.
Due to its ready availability and high chemical reactivity, we
first used N-aminophthalimide 3 as a model system (Scheme 2).
Azide 5 was obtained in three steps and 47% yield from 3 by
condensation with α-bromoacetaldehyde 45 in the presence of
4 Å molecular sieves to give the α-bromohydrazone. Since this
intermediate was found to be very labile, it was reduced without
isolation with NaCNBH3 to give the corresponding bromoethyl
derivative, which was converted to alkyl azide 5 with sodium
azide in DMF.
Department of Chemistry and Center for Chemical Methodologies and
Library Development, 219 Parkman Avenue, 15260 Pittsburgh, PA,
USA. E-mail: pwipf@pitt.edu; Fax: +1 412 624 0787; Tel: +1 412 624
8606
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Dedicated to the memory of Prof. Robert E. Ireland.
§Electronic supplementary information (ESI) available: Synthetic proto-
cols and spectroscopic data. CCDC 868588–868590. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob25353d
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Scheme 3 Failed hydrazone formation.
Scheme 5 Formation of isomeric triazinoisoquinolines under acidic
acetal hydrolysis conditions.
presence of 5 mol% of Cu(I)-catalyst, 10 mol% of picolinic acid,
and 3 equiv of Cs2CO3 in dioxane led to the α-aryl malonate
intermediate, which was used crude after workup. The homo-
phthalimide ring was readily obtained by treatment with catalytic
p-toluenesulfonic acid (p-TSA) in aqueous toluene, which pro-
moted a cascade cyclization–decarboxylation to yield 18 in 73%
over 2 steps.
In preparation for the introduction of the benzylic ketone func-
tion, 18 was converted to thioacetal 20 by treatment with tri-
methylene dithiotosylate 19 (Scheme 5).7 Acetal exchange to the
dimethyl acetal 21 was accomplished with iodobenzenebis-
trifluoroacetate (PIFA) in methanol in the presence of trifluoro-
acetic acid.8 The Staudinger-aza-Wittig reaction of 21 proceeded
smoothly under microwave irradiation conditions to give the
desired triazine 22 in 61% yield, but all attempts to hydrolyze
the acetal to unmask the carbonyl group either decomposed the
product or provided a 2.5 : 1 mixture of the isomeric triazinoiso-
quinolines 23a and 23b in modest 45% combined yield. The
structures of 23a and 23b were unambiguously assigned by
X-ray crystallographic analysis (Fig. 2).
Scheme 4 Preparation of homophthalimide 18 by a key copper-cata-
lyzed C-arylation.
When azide 5 was heated in toluene at 100 °C in the presence
of 2 equiv of PBu3, a clean conversion to the desired triazinone
6 occurred. Alternatively, the hydrazide was N-protected with
benzyl bromide in the presence of tetrabutylammonium hydro-
gen sulfate (TBAHS), and the phosphine treatment afforded the
corresponding triazinone 7 in 97% yield. The N-benzylated tria-
zinone 7 was much easier to isolate and purify than the un-
protected 6.
While the formation of 23b accomplished our goal to access
the DEF ring system of 1, we were unable to identify acetal
hydrolysis conditions avoiding the equilibration of this hetero-
cyclic system to the isomeric 3,4-dihydro-2H-[1,2,4]triazino-
[4,3-b]isoquinoline-6,11-dione 23a. Furthermore, we were
unable to cleave the benzyl protecting group in either 23a or
23b.
Accordingly, we modified the synthetic route shown in
Schemes 4 and 5 by using the p-methoxybenzyl (PMB) pro-
tected azido hydrazine 24 (Scheme 6). Acylation of 15, C-aryla-
tion with malonate 17, and cyclization–decarboxylation
proceeded uneventfully to give homophthalate 25. In two steps,
the benzylic methylene group in 25 was converted to the
dimethyl acetal and the Staudinger-aza-Wittig reaction provided
triazine 26 in high yield. Interestingly, controlled hydrolysis in
cold sulfuric acid removed the PMB group in 72% yield without
cleavage of the dimethyl acetal. The resulting dimethyl acetal 27
The successful conversion of model azido-hydrazide 5 into
triazino[3,2-a]isoindolones 6 and 7 encouraged us to explore the
preparation of triazino[2,3-b]isoquinolines. However, we were
unable to isolate the requisite intermediate α-bromohydrazone 9
from hydrazide 8 under typical condensation conditions with
aldehyde 4 (Scheme 3). While the hydrazone appeared to form,
decomposition during the reaction resulted in the formation of a
complex mixture at workup.
After several unsuccessful attempts to add the azide moiety to
the homophthalimide ring system, we were able to develop a
strategy that installed the cyclic imide on a prefunctionalized
hydrazide (Scheme 4). Protection of 2-hydroxyethylhydrazine
with ethyl pyruvate 10 gave hydrazone 11 in 59% yield. Mesyla-
tion of the alcohol and treatment with NaN3 led to azide 12,
which was selectively benzylated and then hydrolyzed to give
the azido-hydrazine 14. After acylation of 14 with o-iodoben-
zoylchloride 15, a C-arylation6 of diethylmalonate 17 in the
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Fig. 3 X-Ray structure of 28.
Conclusions
We have demonstrated an efficient method to generate azido
hydrazines, thus enabling the application of the Staudinger-aza-
Wittig reaction of imides as a general method for the preparation
of tetrahydro-1,2,4-triazines. For the synthesis of the DEF ring
system of noelaquinone, the Cu(I)-catalyzed C-arylation of
diethyl malonate was used to access the key intermediate homo-
phthalimides 18 and 25. The use of the PMB protective group
and controlled acidic hydrolysis conditions led to the first prep-
aration of the heterocycle 28, previously reported for the DEF
ring moiety of the natural product noelaquinone. In the course of
this synthesis, we also observed the equilibration of triazinoiso-
quinolines 23a and 23b under acidic conditions, most likely via
an ANRORC9 mechanism.
Fig. 2 X-Ray structures of 23a (top) and 23b (bottom).
Acknowledgements
The authors thank the National Institutes of Health
(P50GM067082) for support of this research and Dr. Steven
Geib (University of Pittsburgh) for X-ray analyses.
Notes and references
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